Occult HPT-JT among kindreds provisionally diagnosed with FIHP

The principal clinical tests of affected individuals from kindreds provisionally diagnosed as FIHP to identify incomplete forms of HPT-JT are jaw and renal imaging studies. Prior diagnosis in the proband or any known affected relative in a family with iso­lated HPT of cemento-ossifying fibroma of the maxilla or mandible, the jaw tumor type characteristic of HPT-JT, was sufficient to make a presumptive diagnosis of HPT-JT and ex­clude them the analyses of FIHP kindreds reviewed here. The initial evaluation of one kindred (family 2862) included jaw imaging of the proband only, with normal findings, leading to a provisional diagnosis of FIHP. Sub­sequent investigation revealed that 3 siblings in this kindred developed jaw lesions, in each case determined to be cemen- to-ossifying fibrous tumors by histopathologic analysis, leading to its re-categorization as HPT-JT (Table I). One affected member of kindred 27,000 had had multiple mandibular and maxillary surgeries to remove jaw “cysts” decades earlier; med­ical records documenting the histopathology could not be re­trieved (Table I). Subsequent analysis of germline DNA in this FIHP kindred documented HRPT2 frameshift mutation (Table I).

Table IV – Kindreds with familial isolated hyperparathyroidism and germline CASR gene mutation from the literature.

Kindred

CASR Germline Mutation

Ref

No.

Exon (a)

Base (b)

Consequence Affected domain (c) (d)

1

3

299

T100I

ECD

(34)

2

3

476

L159P

ECD

(11)

3

4

658

R220W

ECD

(11)

4

4

748

E250K

ECD

(11)

5

4

801

V268del-11X273

na

(11)

6

4

1008

K336del

ECD

(34)

7

7

1949

L650P

7TM

(34)

8

7

2065

V689M

7TM

(34)

9

7

2657

R886P

ICD

(11)

Renal imaging, usually by ultrasonography, is routinely per­formed on affected members of kindreds provisionally diag­nosed with FIHP since cysts and solid renal tumors have been associated with HPT-JT. In studies from our center, bilateral renal cysts were found in individuals from three kindreds initially considered as FIHP but subse­quently categorized as HPT-JT (Table I; kindreds 417, 2862 and 27,000), while no such bilateral cysts were found in CaSR mutation-positive or non-syndromic FIHP kindreds. No renal hamartoma, nephroblastoma or renal cell carcinoma, le­sions also reported in occasional association with HPT-JT, has been reported among provisionally diagnosed FIHP kindreds. The probands from 2 non-syndromic FIHP kindreds had renal angiomyolipoma diag­nosed by ultrasound and/or CT scan. Such renal tumors have been rare concomitants of MEN1. Review of the surgical findings and histopathology of parathy­roid tumors from operated members of provisionally diagnosed FIHP kindreds may add evidence for their re-consideration as occult HPT-JT. Cystic parathyroid tumors have been associat­ed with HPT-JT and parathyroid tumors from some kin­dreds initially considered as FIHP and later recognized as in­complete expressions of HPT-JT were noted to have cystic features. At least one FIHP kindred with cystic parathyroid tumors in several affected members, howev­er, has negative germline HRPT2 gene mutational testing and no other features to date suggestive of HPT-JT (Fig. 2). Parathyroid cancer is common in HPT-JT, but very rare among sporadic cases of HPT (0.8%). In this light, it is interesting to note that the presence of parathyroid carcino­ma in some kindreds initially considered as FIHP foreshad­owed their subsequent recognition as expressions of HPT-JT.

Figure 2 - A kindred with non-syndromic familial

Figure 2 – A kindred with non-syndromic familial isolated hyperparathy­roidism, cystic parathyroid tumors, and negative germline HRPT2 gene mutation testing. This kindred (28,200) with non-syndromic FIHP has been previously reported  (Table I). Individuals II-6 and III-5 were separately reported earlier as the father and daughter in Shallow and Fry. Filled symbols indicate individuals with primary HPT, and a “C” indi­cates that cystic parathyroid tumors were noted at surgery. Original surgi­cal records and parathyroid histopathology reports were not available for individuals II-2, II-6 and II-3. Square symbols indicate males, and round symbols indicate females. A diagonal slash mark through the symbol means the individual is deceased. The arrow indicates the proband.

Table V – Kindreds with familial isolated hyperparathyroidism and germline HRPT2 gene mutation from the literature.

Kindred

HRPT2 Germline Mutation

Ref

Note

No.

Exon/

Base

Consequence

Intron

(IVS)

(a)

(b)

(c)

1

1

34

34 del7

(8, 11)

d

2

IVS1

131+1

abnl splicing

(26, 49)

3

2

191

L64P

(24, 25, 27)

4

IVS2

237+1

abnl splicing

(27)

5

7

679

679ins2

(8, 11, 29, 55)

e

Germline DNA analysis for HRPT2 gene mutation may also identify occult HPT-JT among provisionally diagnosed FIHP kindreds even though such testing has only some 50% sensi­tivity in full-featured HPT-JT families. Five unique germline HRPT2 mutations have been identified in eight kindreds initially considered as FIHP (Table V). Three of these mutations are re­current: a point mutation at a splice junction in HRPT2 IVS1 that uncovers a cryptic exon 1 donor splice site in two ap­parently unrelated families with isolated HPT; an exon 2 L64P missense mutation in two unrelated FIHP families; and a 2-bp insertion in HRPT2 exon 7 in three appar­ently unrelated FIHP kindreds. The latter exon 7 mutation (679insAG) has also been described in the germline of patients with full-featured HPT-JT and seemingly spo­radic parathyroid carcinoma. The types of germline HRPT2 mutation in kindreds initially considered as FIHP re­semble those in HPT-JT with the majority resulting in frameshift or splicing abnormalities that cause incomplete parafibromin protein expression (Table V).
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